Alzheimer's disease (AD) is a devastating illness, estimated to affect 5 million patients in the United States alone and projected to increase dramatically over the next decades as the population ages unless preventive measures can be developed. While there is no currently approved treatment that modifies the underlying cause of the disease, there is intense activity towards developing anti-amyloid beta therapies. Recent trials of such treatments however have had no, or very limited, success in altering the course of AD. It is likely that these failures to benefit individuals with clinically diagnosed AD occurred because the treatments were administered too late in the disease process. We have preliminary evidence that selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with lower A[unreadable] plaques in the human brain. We also found that in a transgenic mouse model of AD two SSRI antidepressants acutely reduced brain A[unreadable] levels by 25% and direct infusion of serotonin reduced A[unreadable] levels by 30% in vivo without affecting A2 elimination rates, suggesting that serotonin signaling is responsible for the reduction in A[unreadable] generation. We now have data demonstrating that prospective treatment with 16 weeks of citalopram significantly reduced plaque burden in AD mice. The current proposal will test whether clinically relevant doses of an SSRI reduce A[unreadable] production in healthy human subjects. This is made possible by the recent development of a stable isotope labeling kinetic (SILK) technique by our colleagues here at Washington University. The SILK assay assesses A[unreadable] pharmacodynamics in human subjects. It uses administration of 13C6-leucine and monitors the rate of 13C6-labeled A[unreadable] appearance in the CSF to determine the rate of A[unreadable] synthesis and clearance. We propose to conduct a randomized placebo-controlled comparison in 12 subjects ages 18-40 who will undergo assessment of A[unreadable] production during a 36-hour stay in our clinical research unit. Each subject will be randomized to treatment with a 4 week course of placebo or 20 mg/day of citalopram, prior to the initiation of the 13C6-leucine administration and CSF sampling. Hypothesis: Compared to the subjects receiving placebo, subjects receiving citalopram will show significantly (p<0.05) lower A[unreadable] production as measured by SILK. Significance: If our hypothesis is supported and citalopram is associated with a substantial reduction in A[unreadable] production, we will use this data to assess the value of a prospective trial to test whether SSRIs reduce the rate of A[unreadable] plaque formation. While many factors go into the design of such a trial, the potential significance for preventing AD would be large. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a devastating illness, projected to increase dramatically in the next decades. Currently there is no approved treatment that modifies the underlying cause of the illness. We have preliminary data in humans and animal models that SSRI antidepressants can lower the amount of Amyloid beta (A[unreadable]), the peptide that plays a critical and early role in the development of AD. This project will determine whether compared to placebo, SSRI antidepressants lower the production of A[unreadable] in human CSF.